4-thiazolidone derivatives and process for preparing the same



Patented Dec. 23, 1952 4-THIAZOLI DONE DERIVATIVES AND PROC- ESS FORPREPARING THE SAME Loren M. Long, Grosse Pointe Woods,,and Harvey D.Troutman, Ferndale, Mich., assignors to Parke, Davis & Company, Detroit,Mich., a corj poration of Michigan NO Drawingpplication-April 5, 1948,

' 1 Serial No. 19,174. w

This invention relates to a new class of therapeutically valuableheterocyclic organic conipounds and to methods for obtaining the same.More particularly, the invention relates to a class of heterocyclicorganic compound composed of certain substituted 4-thiazolidones and4-thiazolidone-l-dioxides-having the general formula,

R-CHNR1 Rn Rs where R is a, substituted or unsubstituted phenyl radical,a Z-furyl radical or a Z-thienyl radical; R1 is a lower alkyl, adialkylamino substituted alkyl, a lower alkenyl or a lower aralkylradical; R2 and R3 are the same or diiferent and-represent hydrogen orlower alkyl radicals and X is S or S02-. Some examples of thesubstituents which may be presentin the phenyl ring of the productswherein R is a substituted phenyl radical are halogen, nitro, amino,lower alkyl and lower alkoxy groups.

In accordance with the invention, an a-mercapto-acetic acid or esterthereof is reacted with an azomethine compound to obtain thecorresponding 4-thiazolidone compound which, if desired, can beconverted to the corresponding 4- thiazolidone-l-dioxide by theoxidation methods herein-after described. These transformations may bediagrammatically illustrated as follows:

where R4 is hydrogen or a lower alkyl radical and R, R1, R2 and Rs.have. the same significance as given above. 7 V j V 'I'hereactionbetween the a-mercapto'acetic acid compound and the. azomethinecompound, represented by A in the above diagram; can be carried outeither in the presence orabsence'of- 13 Claims. (01. 260- 301") an inertorganic solvent and at a temperature be; tween about 25 and 200 C. Someexamples' of; the solvents which can be used are benzene, to1uene,xylene, ethanol, n-propanol, petroleum ether, chloroform and the like.The preferred starting materials for the reaction are the a-mercaptoacetic acid ester compounds since the intermediate condensation productsformed from the ester compounds cyclize much more readily and at lowertemperatures than do the corresponding intermediate products derivedfrom the free acid starting materials.

The ,oxidationof the 4-thi-azolidone compounds to the corresponding4sthiazolidone-1-dioxides, represented by B in the above diagram, iscarriedout below C. under acidic conditions using hydrogen peroxide orchromicacid a'sthe oxidizing agent.' Water, anhydrous organicsolvents ormixtures of the same can be used a reaction media. When hydrogenperoxide, the preferred oxidizing agent, is used itis preferable to keepthe amount of water present in the reaction mixture at a'minimumandjwherie the solvent used is not acidic per se, to add a man amountofmin'e'ral acid to the reaction mixture. Some examples of the organicsolvents which can be used with this oxidizing agent are acetone, methylethyl ketone, diethyl ketone, ethanol, n-propanol, acetic acid; aceticanhydride and the like. I Y The substituted 4-thiazolidone' andl-thiazoli done-l-dioxide products of the invention are particularlyuseful in the treatment, of petit mal epilepsy due to a combination; of,their unique anticonvulsant activity, low toxicity and-freedom fromdepressive side effects. Some of thesenovelf products alsopossess arelatively highdegre'e of analgetic activity and are therefore useful inre-' lieving pain. l The invention is illustrated by the, followingexamples.

, Example! (a) '74 g. of methyl thioglycolate is added slowly to 107 g.of refluxing benzylidene'n-propylamine and refluxing continued(temperature about -60 C.) for about two and one-half hours while astream of nitrogen is passed through the mixture. After the reactionmixture has cooled, 250 00.015 water is added and the mixture steamdistilled until about two liters of distillate is collected. The residuein the still is cooled, the solid collected and distilled with 350 cc.of toluene until no more water appears in the condensate. The toluenesolution is decolorized with charcoal, filtered and the toluenedistilled from the filtrate in vacuo. The residue which consists of thedesired 2-phenyl-3-n-propyl-4-thiazolidone of formula,

O-on-n-omomom crystallizes on cooling as a pal yellow solid.Recrystallization from benzene yields the, pure white crystallineproduct melting at 67-8" C.

By substituting an equivalent amount of benzylidene methylamine,ethylamine or n-butylamine for the benzylidene n-propylamine used in theabove procedure one obtains 2-phenyl-3- methyl-4-thiazolidone (purifiedby distillation; B. P. 1479 C./ 1.9 mm.), 2-phenyl-3-ethy1-4rthiazolidone (M. P. 54-55 C.) and 2-phenyl-3- n-butyl-i-thiazolidone (M.P. 56.5-57.5 0.), respectively.

, (b) 125. cc. of 30% aqueous hydrogen peroxide is added in one portionto a mixture consisting of 60 g. of 2-phenyl-3-n-propyl-4-thiazolidone,500 cc. of glacial acetic acid and 125 cc. of acetic anhydride. Thetemperature of the reaction mixture rises to about 55 C. and ismaintained atthis point until the exothermic reaction ceases. Thereaction mixture is evaporated to dryness in vacuo below 60 C.. and theresidue heated under reflux with 200 cc. of methanol and 800 cc. ofwater. The mixture is cooled and the crude 2-phenyl-3-npropyl-4-thiazolidone-l-dioxide collected. Recrystallization.from methanol yields the desired product in the form of white crystalsmelting at 108-11-0 C. the formula of. this prodand2-phenyl-3-n-butyl-4-thiazolidone-1-dioxide (M. P. 86-7 C.),respectively.

' Example 2 53 g. of methyl th-ioglycolate is added slowly to 72.5 g. ofrefluxing benzylidene allylamine and. refluxing continued for about twoand one-half hours while a stream of nitrogen is passed through themixture. After the reaction mixture has cooled, 200 cc. of water isadded and the mixture steam distilled until about two liters ofdistillate is collected. The residue is cooled and the solid collected.300 cc. of toluene is added to the solid and the toluene distilled untilno more water appears in the condensate. The residual solution isdecolorized with carbon and the toluene distilled in vacuo to obtain thedesired 2-phenyl-3-a1ly1-4-thiazolidone of for- Recrystallization of thecrude product from benzene yields the pure thiazolidone melting at ell-9C.

4 Example 3 (a) 53 g. of methyl thioglycolate is added slowly to 98 g.of benzilidine benzylamine at about 155-60 C. and heating continued forabout twoand one-halfhourswhile a stream of nitrogen is passed throughthe mixture. The reaction mixture is cooled, treated with 250 cc. ofwater and steam distilled until about two liters of distillate has beencollected. The residue is cooled and the crude2-phenyl-3-benzyl-4-thiazolidone of formula,

collected. The crude product is dried by adding it to.25(l cc. oftoluene and distilling off the toluene until no more water, appears inth condensate. The dry toluene solution is decolorized with carbon, thetoluene distilled in vacuo and the residual product purified byrecrystallization from benzene: M. P. 153-4 C.

(b) cc. of 30% aqueous hydrogen peroxide is added in one portion to amixture consisting of- 60 g. of 2-phenyl-3-benzyl-4-thiazolidone, 500.cc. of glacial acetic acid and 125 cc. of acetic anhydride and thetemperature of the reaction mixture maintained at about 60 C. forone-half hour. The reaction mixture is evaporated to dryness in vacuobelow 60 C. and the residue heated under reflux with one liter of 20%methanol. The mixture is cooled, the crude 2-phenyl-3-benzyl-4-thiazolidone-l-dioxide collected and purified byrecrystallization from alcohol; M. P. 127-8 C. The formula of thisproduct is:

Example 4 (a) 63.5 g. of methyl thioglycolate is added slowly to 144 g.of 3-nitrobenzylidine benzylamine at C. and heating continued for aboutthree hours while passing a stream of nitrogen through the mixture. Thereaction mixture is cooled, treated with 250 cc. of water and steamdistilled. The residue is cooled and the crude product collected. Thecrude product is dissolved in 350 cc. of toluene and dried by distillingoff the toluene until no more water appears in the distillate. Thesolution is decolorized with charcoal and the toluene distilled underreduced pressure. The crystalline residue which consists of the desired2- (3'-nitrophenyl) 3 -benzyl 4 thiazolidone of l lo:

is purified by recrystallization from benzene; M. P. 113-4 C.

(b) A mixture consisting of 60 g. of 2-(3'-nitrophenyl)-3-benzyl-4-thiazolidone, 440 g. of zinc dust, 15 g. ofcalcium chloride, 215 cc. of water and 1300 cc. of 95% ethanol isrefluxed for about twelve hours, filtered and the filtrate evaporated toa volume of one liter. Two liters of water is added and the whiteproduct which precipitates collected. This product which is 2- 8(3'-aminophenyl) 3 -benzyl 4 thiazclidone or formula,

i i i= NH: \O

can be purified by recrystallization from ethanol; M. P. 132-3 C.

Example (:1) '53 g. of methyl thioglycolate is added slowly to 76.8 g.of d-chlorobenzylidene methylamine at 155 C. and the mixture heated atthis temperature for about two and a half hours while a stream ofnitrogen is passed through the mixture. After the reaction mixture hascooled, 250 cc. of wateris added and the mixture steam distilled untilabout two liters of distillate is collected. The residue in the still iscooled, the solid collected and distilled with 350 cc. of toluene untilno more water appears in the condensate. The toluene solution isdecolorized with carbon, the toluene evaporated under reduced pressureand the residual crude 2-(4'-chlorophenyl)-3- methyl-i-thi-azolidone offormula,

purified by distillation in high vacuo; B. P. 184-5" C./3 mm. 1

By employing 4-chlorobenzylidene ethylamine or n-propylamine in theabove procedure instead of a-chlorobenzylidene methylamine one obtains 2(4'-chlorophenyl) 3 ethyl 4 thiazolidone (M. P. 69-70 C.) and2-(4'-chlorophenyl)-3-npropyl-i-thiazolidone (M. P. 645 C.) respective:-ly. These products which are solids can either be purified bydistillation in vacuo as described above or by recrystallization from anorganic solvent such as bezene.

(b) 125 cc. of 30% aqueous hydrogen peroxide is added to a mixtureconsisting of 60 g. of 2-(4- chlorophenyl) -3-methyl-4-thiazolidone, 500cc. of glacial acetic acid and 125 cc. of acetic anhydride. Thetemperature of the reaction mixture rises to about 60 C. and ismaintained at this point until the exothermic reaction ceases. Thereaction mixture is evaporated to dryness in vacuo below 60 C. and theresidue refluxed with about one liter of 20% methanol. The mixture iscooledand the crude 2-(4-cholorphenyl) -r3-methyl-4-thiazolidone-1-dioxide collected purifled by recrystallizationfrom methanol; M. P. 155-6 0.

By substituting 2-(4'-chlorophenyl-3-ethyl-4- thiazolidone for the3-methy1 derivative used in the above procedure one obtains2-(4'-chlorophenyl)-3-ethyl-'4-thiazolidone-l-dioxide; M. P. 145-6" 0.

Example 6 53 g. of methyl thioglycolate is added slowly to 94 g. of3.4-dichlorobenzylidene methylamine and the mixture heated at about 160C. for two hours while a stream of nitrogen is passed through theliquid. The reaction mixture is cooled, treated with about 250 cc. ofwater and steam distilled until about two liters of distillate iscollected. The residue is cooled and the 2-(3',4'-dichlorophenyl)-3-methyl-4-thiazolidone of formula, i

taken up in toluene and the layer separated from the aqueous solution.The toluene is distilled to obtain the desired thiazolidone as a lightcolored non-distillable oil.

thioglycolate and 54 g. of furfurylidene methyl- :[amine is heated underreflux for about two to three hours while a stream of nitrogen isbubbled through the solution. The reaction mixture is cooled, treatedwith 250 cc. of water and steam distilled until about two liters ofdistillate has been collected. The residue is cooled and the solidcollected. The solid" product is treated with about 350 cc. of benzeneand the benzene distilled until no more water appears in the distillate.The residual solution is decolorized with carbon, the benzene evaporatedfrom the filtrate in vacuo and the residue distilled under high vacuo toobtain the desired 2-(2'-furyl)-3- methyll-thiazolidone; B. P. 134-40C./3 mm. On standing the product crystallizes to a white solid meltingat 78 C. after recrystallization from benzene-ethyl acetate mixture. Itsformula is:

L oin-r pen:

' (b) cc. of 30% hydrogen peroxide is added to a mixture consisting of60 g. of 2-(2'-furyl)- 3-methyl-4 thiazolid'one, 500 cc. of glacialacetic acid and 125 cc. of acetic anhydride. The temperature of thereaction mixture is maintained at about 60 C. for one-half hour and thenevaporated to dryness in vacuo below 60 C. The residue is heated underreflux with about one liter of 20% methanol, the mixture cooled and thecrude 2-(2'-furyl)-3-methyl-4-thiazo1idonel-dioxide collected andpurified by recrystallizationi from methanol. The formula of thisproduct s:

Ewample 8 (a) 0.5 g. of anhydrous calcium chloride is added to a mixtureconsisting of 63.6 g. of methyl thioglycolate and 75 g. of2-thienylidene methylamine and the resulting mixture heated under refluxfor about two and one-half hours while passing a stream of nitrogenthrough the liquid. The mixture is cooled, treated with about 250 cc. ofwater and steam distilled until two liters of distillate is collected.The residue is cooled and the solid product collected. The solid isdissolved in 200 cc. of benzene and the benzene distilled until water nolonger appears in the distillate. The remaining benzene is distilled invacuo and the brownishyellow solid which forms on cooling the residuetaken up in and recrystallized from benzene-ethyl acetate'mix- '7 ture.The recrystallized white solid which melts at 65-6 C. is2-(2'-thienyl)-3-methyl-4.-thiazolidone of formula,

(b) 125 cc. of 30% aqueous hydrogen peroxide is added to a mixtureconsisting of 60 g. of 2- (2-thienyl) -3-methyl-4-thiazolidone, 500 cc.of glacial acetic acid and 125 cc. of acetic anhydride and thetemperature of the resulting mixture maintained at about 60 for aboutone-half hour; The reaction mixture is evaporated to dryness below 60 C.in vacuo and the residue boiled with about one liter of 20% methanol.The methanol mixture is cooled and the crude 2-(2"-thienyl) -3-methyl-4-thiazolidone-1-dioxide collected and purified byrecrystallization from methanol. The formula of this product is: 1

Example 9 (a) 53 g. of methyl thioglycolate is added slowly to 101 g. ofbenzylidene B-diethylaminoethylamine and the mixture allowed to warmspontaneously to about 75 C. The mixture is allowed to stand at roomtemperature for twenty-four hours, treated with about 200 cc. of waterand steam distilled until about two liters of distillate has beencollected. The residue is cooled, extracted with ether and the etherdistilled from the combined extracts after drying. The residue isdistilled under high vacuo to obtain the desired2-pheny1-3-B-diethylaminoethyll-thiazolidone as alight yellow oil; 13.P. 1658 C./2 mm. The formula of this product s o=o (b) 125 cc. of 30%aqueous hydrogen peroxide is added to a mixture consisting of 60 g. of 2pheny1 3 e diethylaminoethyl-a-thiazolidone, 500 cc. of glacial aceticacid and 125 cc. of acetic anhydride and the resulting mixture heated atabout 60 C. for one-half hour. The reaction mixture is evaporated todryness in vacuo at a low temperature and the residue treated with about400 cc. of water. Dilute sodium hydroxide solution is added to thesolution and the desired2-phenyl-3-B-diethylaminoethyl-4-thiazolidone-l-dioxide of formula,

Earample 10 (a) 67 g. of ethyl a-mercaptopropionate is added slowly to74 g. of 2-methyl benzylidene ethylamine and the mixture heated at aboutC. for three hours-while a stream of nitrogen is passed through theliquid. The reaction mixture is cooled, treated with about 200 cc. ofwater and steam distilled. The residue is cooled and the solid productcollected. The solid is dissolved in about 300 cc. of toluene and thetoluene solution dried by distillation. The remaining toluene isdistilled in vacuo and the residual 2- (2 -methylpheny1)-3-ethyl-5-methyl- 4-thiazolidone purified by recrystallization frombenzeneethyl acetate mixture. The formula of this product is:

(b) 60 g. of 2-(2'-methyl-phenyl)-3-ethyl-5- methyl-4-thiazolidone isdissolved in a mixture consisting of 500 cc. of glacial acetic acid andcc. of acetic anhydride and the resulting solution treated with 125 cc.of 30% aqueous hydrogen peroxide. The reaction mixture is heated atabout 60 C. for one hour and then evaporated to dryness in vacuo at atemperature below about 60 C. The residue is boiled with dilutemethanol, the mixture cooled and the desired 2-(2 methylphenyl) 3ethyl-5-methyl-4-thiazolidone-l-dioxide of formula,

' CHI GCH N-(MH! o on collected.

Example 11 (a) '74 g; of ethyl d-mercap'to isobutyrate is added slowlyto 81 g. of 4-methoxy benzyldene ethylamine and the mixture heated at125 C. for about two hours while a stream of nitrogen is passed throughthe solution. The reaction mixture is cooled, treated with about 250 cc.of water and steam distilled until about two liters of distillate hasbeen collected. The residue is cooled and the crude2-(4-methoxyphenyl)-3- ethyl 5,5 dimethyli-thiazolidone collected. Thecrude product is dried by distillation with toluene and purified, afterevaporation of the toluene, by recrystallization from benzene. Theformula of this product is:

C C CHa By oxidizing 2- (4-methoxyphenyl) -3-ethyl-5,5-dimethyl-4-thiazolidone with hydrogen peroxide under the conditionsdescribed in the preceding example one obtains 2-(4metho'xyphenyl) .3-ethyl-5,5-dimethyl-4-thiazo1idonel-dioxide.

Some further examples of the product which can be obtained by themethods described above are:

1.- 2 (3*,4 dimethylphenyl) 3-methyl-5- ethyl-4-thiazolidone.

2. 2 (324' dimethylphenyl) 3-methyl-5- ethyl--thiazolidone-l-dioxide.

9.. 2-(2'-thienyl) -3-benzyl-'4'-thiazo1idone.

4. 2-(2'-thienyl)-3-benzy1-4-thiazolidone 1 dioxide.

5. 2-(2'-thienyl) -3-a1lyl-5-methyl 4-thiazolidone.

6. 2-(4' methylphenyl)-3-- -dimethylaminopropyl-4-thiazolidone.

7. 2-(4'methylphenyl)-3-'y-dimethylaminopropyl-4-thiazolidone-1-dioxide.

8. 2 (2' furyl)-3-phenylethyl-5-methyl-4- thiazolidone.

9. 2 (2' furyl)-3-phenylethyl-5-methyl-4- thiazolidone-1-dloxide.

10. 2 (2' furyl)-3-fl-dimethylaminoethyl-5, 5-dimethyl-4-thiazolidone.

11. 2 (2' furyl)-3-B-dimethylaminoethyl5,5-dimethyl-4-thiazolidone-1-dioxide.

12. 2 (4' chlorophenyl)-3-ethyl-5-methyl- 4-thiazolidone.

13. 2 (4 chlorophenyl)-3-ethyl-5-methyl- 4-thlazolidone-1-dioxide.

14. 2 (4' chlorophenyl)-3-benzyl-5-n-propyl-4-t-hiazolidone.

15. 2 (4 chlorophenyl)-3-benzyl-5-n-propyl-4-thiazolidone-1-dioxide.

16. 2 (3',4' dimethoxyphenyl)-3-methyl-4- thiazolidone.

17. 2 (3',4 dimethoxyphenyl)-3-methyl-4- thiazolidone-l-dioxide.

What we claim is:

1. A compound of the formula,

n-on-n-m =0 R Rs where R is a member of the class consisting ofmonocarbocyclic aryl, 2-furyl and 2-thienyl radicals, R1 is a member ofthe class consisting of lower alkyl, lower dialkylamino substitutedlower alkyl, lower alkenyl and lower aralkyl radicals, R2 and Rs aremembers of the class consisting of hydrogen and lower alkyl radicals andX is a member of the class consisting of S- and 2. A compound of theformula,

where R is a monocarbocyclic aryl group.

3. A compound of the formula,

4. A compound of the formula,

where R is a monocarbocyclic aryl group.

5. A compound of the formula.

6. A compound of the formula,

mOorz-n-on.

7. A compound of the formula,

8. A compound of the formula,

OCH-M4311.

i a. C131: 9. 2-phenyl-3-ethyl-4-thiazolidone. 10.2-phenyl-3-ethyl-4=-thiazo1idone 1 d1- oxide.

11. Process for obtaining a compound of formula,

RCH--NRi i Rg R;

R2 HS(IJOOOR4 with an azomethine compound of formula,

R-CH=NR1 to obtain a 4-thiazolidone compound of formula,

RCHNR1 Ra Ra and thereafter oxidizing said 4-thiazolidone compound tothe corresponding 4-thiazolidone-1-dloxide of formula,

where R is a member of the class consisting of monocarbocyclic aryl,2-furyl and 2-thieny1radicals, R1 is a member of the class consisting oflower alkyl, lower dialkylamino-substituted lower 11 alkyl, loweralkenyl and lower aralkyl radicals and R2, R3 and R4 are members of theclass consisting of hydrogen and lower alkyl radicals.

13. Process for obtaining a 4-thiazolidone-ldioxide compound of formula,

RQHN-R1 which comprises oxidizing a 4-thiazolid0ne compound of formula,

RCHNR1 under acidic conditions with an oxidizing agent of the classconsisting of hydrogen peroxide and chromic acid, Where R is a member ofthe class consisting of monocarbocyclic aryl, Z-furyl and 2- thienylradicals, R1 is a member of the class consisting of lower alkyl, lowerdialkylamino substituted lower alkyl, lower alkenyl and lower aralkylradicals and R2 and R3 are members of the class consisting of hydrogenand lower alkyl radicals.

LOREN M. LONG.

HARVEY D. TROUTMAN.

No references cited.

1. A COMPOUND OF THE FORMULA,